While osteoporosis has been recognized as a major public health problem in women, it is now clear that men also develop the disease. Moreover, our work over the previous funding cycle and the findings of others have implicated sex steroid and, in particular, estrogen (E) deficiency as playing a significant role in mediating age-related bone loss not only in women, but also in men. However, it is much more difficult to study sex steroid effects on bone in aging men as compared to postmenopausal women, since elderly men have only partial sex steroid deficiency, whereas postmenopausal women are almost completely sex steroid deficient. Thus, the development of an experimental approach by our group over the previous funding cycle that produces reversible, short term sex steroid deficiency in elderly men and allows for selective E and/or testosterone (T) replacement represents a significant methodological advance that we intend to exploit further in the proposed studies. We will combine this powerful experimental design with novel techniques we have recently developed in our laboratories that now allow us to assess protein and gene expression of key factors regulating bone resorption by bone marrow cells in vivo to study three important areas where E has been shown to play an important role in regulating bone metabolism in women, but where there is still a paucity of data on E (or T) effects in men. There are: (1) the mechanism(s) of the direct actions of sex steroids on bone resorption; (2) possible extra-skeletal effects of E and/or T on the intestine and the kidney; and (3) the modulation, by E and/or T, of the pro-resorptive effects of parathyroid hormone (PTH) on bone. Thus, our Specific Aims are to test the hypotheses that, in normal elderly men, both E and T (in the absence of aromatization to E) will independently (1) inhibit receptor activator of NF-KappaB ligand (RANKL) and RANK expression by bone marrow cells in vivo; (2) enhance intestinal calcium absorption and renal tubular calcium reabsorption; and (3) attenuate PTH-induced increases in bone resorption. Aims 1 and 3 also include detailed studies examining the expression, in the appropriate bone marrow cells, of genes for key cytokines regulating bone resorption, both under basal conditions and following a PTH infusion. These studies are a logical extension of our previous work, and the results should have significant implications for our understanding of sex steroid regulation of the male skeleton and of age-related bone loss in men.